MicroRNA-504 functions as a tumor suppressor in hepatocellular carcinoma through inhibiting Frizzled-7-mediated-Wnt/β-catenin signaling

Quan, Hui; Li, Bo; Yang, Jianjun

doi:10.1016/j.biopha.2018.07.150

Cited by 34 publications

(21 citation statements)

References 45 publications

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“…Recently, investigations have implicated the tumor-suppressive role of miR-504 in human cancers, providing evidence that this miRNA can repress cell proliferation and invasion in both hypopharyngeal cell carcinoma and hepatocellular carcinoma (HCC) [30, 31]. Similarly, miR-504 is downregulated in non–small cell lung cancer tissue and inhibits cell proliferation, invasion, and EMT by targeting LOXL2 (lysyl oxidase–like 2) [32].…”

Section: Discussionmentioning

confidence: 99%

miR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt–β-catenin pathway

Liu

Guan

et al. 2019

J Exp Clin Cancer Res

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Background MicroRNAs (miRNAs) play crucial roles in tumor initiation and development. Previously, we indicated that miR-504 is downregulated and suppresses tumor proliferation in glioblastoma (GBM). However, the regulation and relevant mechanism of miR-504 in GBM mesenchymal (ME) transition remain unclear. Methods Transcriptome and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. The potential functions of miR-504 were predicted using gene ontology analysis. GBM cell migration and invasion were examined using wound healing and Transwell assays. Epithelial–mesenchymal transition (EMT) progression in GBM cell lines was detected with immunofluorescence and western blotting. The stemness activity of glioma stem-like cells (GSCs) was assessed by sphere formation assay and tumor xenograft model. miR-504 binding to the FZD7 (frizzled class receptor 7) 3′ untranslated region (3′UTR) was validated using dual luciferase reporter assay. TOP/FOP Flash assays were conducted to determine the effects of miR-504 on Wnt/β-catenin signaling. Results Analysis of TCGA transcriptomic data showed that low miR-504 expression correlated with ME subtype transition and poor survival in patients with GBM. Functional experiments showed that miR-504 overexpression suppressed malignant behaviors of GBM cells, such as migration, invasion, EMT, and stemness activity. Furthermore, miR-504 was a negative regulator of the Wnt–β-catenin pathway by directly repressing FZD7 expression, and FZD7 overexpression reversed the EMT inhibition caused by miR-504. Moreover, the low miR-504/FZD7 expression ratio was a ME subtype marker and could serve as a significant prognostic indicator and predict the clinical outcome of chemotherapy and radiotherapy for patients with GBM in TCGA dataset. Conclusions Our results suggest that miR-504 suppresses the aggressive biological processes associated with the ME phenotype of GBM and could be a potential candidate for therapeutic applications in these malignant brain tumors. Electronic supplementary material The online version of this article (10.1186/s13046-019-1370-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

miR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt–β-catenin pathway

Liu

Guan

et al. 2019

J Exp Clin Cancer Res

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“…In osteosarcoma, miR-504 directly targeted tumour protein p53-inducible nuclear protein 1 ( TP53INP1 ), which enhanced osteosarcoma growth and promoted distant metastases [51]. In addition, miR-504 expression levels are frequently downregulated in both hepatocellular carcinoma (HCC) tissues and cell lines [52]. MiR-504 also functions as a tumour-suppressive miRNA that inhibits the proliferation and invasion of HCC cells by targeting Frizzled-7 ( FZD7 ) and inhibiting Wnt/β-catenin signalling.…”

Section: Discussionmentioning

confidence: 99%

The expression of circulating miR-504 in plasma is associated with EGFR mutation status in non-small-cell lung carcinoma patients

Szpechcinski¹,

Florczuk²,

Duk³

et al. 2019

Cell. Mol. Life Sci.

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MicroRNAs (miRNAs), key regulators of gene expression at the post-transcriptional level, are grossly misregulated in some human cancers, including non-small-cell lung carcinoma (NSCLC). The aberrant expression of specific miRNAs results in the abnormal regulation of key components of signalling pathways in tumour cells. MiRNA levels and the activity of the gene targets, including oncogenes and tumour suppressors, produce feedback that changes miRNA expression levels and indicates the cell’s genetic activity. In this study, we measured the expression of five circulating miRNAs (miR-195, miR-504, miR-122, miR-10b and miR-21) and evaluated their association with EPIDERMAL GROWTH FACTOR RECEPTOR ( EGFR ) mutation status in 66 NSCLC patients. Moreover, we examined the discriminative power of circulating miRNAs for EGFR mutant‐positive and -negative NSCLC patients using two different data normalisation approaches. We extracted total RNA from the plasma of 66 non-squamous NSCLC patients (31 of whom had tumours with EGFR mutations) and measured circulating miRNA levels using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The miRNA expression levels were normalised using two endogenous controls: miR-191 and miR-16. We found significant associations between the expression of circulating miR-504 and EGFR -activating mutations in NSCLC patients regardless of the normalisation approach used ( p = 0.0072 and 0.0236 for miR-16 and miR-191 normalisation, respectively). The greatest discriminative power of circulating miR-504 was observed in patients with EGFR exon 19 deletions versus wild-type EGFR normalised to miR-191 (area under the curve (AUC) = 0.81, p < 0.0001). Interestingly, circulating miR-504 levels were significantly reduced in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS )-mutated subgroup compared to EGFR -mutated patients ( p < 0.0030) and those with EGFR/KRAS wild-type tumours ( p < 0.0359). Our study demonstrated the feasibility and potential diagnostic value of plasma miR-504 expression analysis to distinguish between EGFR -mutated and wild-type NSCLC patients. However, quality control and normalisation strategies are very important and have a major impact on the outcomes of circulating miRNA analyses.

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“…miRNA dysregulation is closely associated with a variety of cancer types, and previous studies have revealed that miRNAs may be associated with tumor progression and prognosis (19)(20)(21). Comprehending the molecular mechanism underlying the influence of miRNAs in the progression of cancer may help identify novel treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

miR‑320/ELF3 axis inhibits the progression of breast cancer via the PI3K/AKT pathway

Zhang

Geng

et al. 2020

Oncol Lett

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There is increasing evidence demonstrating that disorders affecting microRNAs (miRs) influence tumorigenesis and progression, which results in a poor prognosis in patients with breast cancer (BC). In the present study, the precise molecular mechanism underlying the role of miR-320 in the progression of BC was investigated. Reverse transcription-quantitative PCR was conducted to determine mRNA expression, and western blot analysis was used to test protein levels. An MTT assay was conducted to detect cell viability and Transwell assays were used to analyze cell migration and invasion abilities. Furthermore, E74-like factor 3 (ELF3) protein density was tested via immunohistochemistry. Tumor volume was detected by xenograft tumor formation assay. The current results indicated that miR-320 expression was downregulated in BC tissues and cells, and was associated with a poor prognosis of patients with BC. Overexpression of miR-320 inhibited cell proliferation, migration and invasion via inhibition of the epithelial-mesenchymal transition and the PI3K/AKT signaling pathway in BC cells. Furthermore, it was revealed that the tumor size and weight were smaller in nude mice that had been transfected to overexpress miR-320. The luciferase reporter assay demonstrated the direct binding of miR-320 to the 3' untranslated region of ELF3 mRNA, which may further downregulate ELF3. Overall, the present results provided evidence that miR-320 may be a tumor suppressor in BC, and that the miR-320/ELF3 axis regulated tumor progression via the PI3K/AKT signaling pathway, which may represent a novel treatment strategy for BC.

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MicroRNA-504 functions as a tumor suppressor in hepatocellular carcinoma through inhibiting Frizzled-7-mediated-Wnt/β-catenin signaling

Cited by 34 publications

References 45 publications

miR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt–β-catenin pathway

miR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt–β-catenin pathway

The expression of circulating miR-504 in plasma is associated with EGFR mutation status in non-small-cell lung carcinoma patients

miR‑320/ELF3 axis inhibits the progression of breast cancer via the PI3K/AKT pathway

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